J. Org. Chem. 1982,47, 2214-2215
2214
with a thermometer, mechanical stirrer, condenser, baffle, and Nzinlet (vented through a safety bubbler) was charged with 30 mmol (10.5 g) of 2, followed by the addition of 400 mL of 30% HzSOI. The suspension was heated to 107 "C (reflux) with rapid stirring until the mixture became a homogeneous orange solution (-1 h). Then 1.0 g of SG Extra charcoal was added, and the mixture was heated at reflux for 15 min, filtered over Celite, and then cooled to room temperature, whereupon the organic product was extracted into CHzClz(3 X 100 mL). This CHzClzsolution was extracted first with 10% Na2C03solution (2 X 25 mL) and then with HzO (2 x 25 mL) and dried over KzC03. The dried solution was placed in a 500-mL distillation flask with 100 mL of hexane. Atmospheric distillation of -350 mL of solvent, followed by cooling to 0 "C, produced crude solid TMBA. The crude solid was dissolved in boding hexane. Insolubles, 0.5 g, were filtered and identified as the starting material 2 (accounting for -5% of 2). The filtered hexane solution was cooled, producing 5.6 g (95% yield) of white TMBA, mp 75-77 OC, which was spectroscopically identical with an authentic sample of commercially available material from the Monsanto Co. Inc.
Scheme I
r
1
VHCOR
I
NHCOR
2 NHCOR
I
3
Scheme 11
Registry No. 1, 86-81-7; 2, 81340-18-3; 3, 4521-61-3; quinoline, 91-22-5.
New Method for the Synthesis of Chloro-Substituted Dibenzo[ b,f][1,4,5]thiadiazepines and Their 5,6-Dihydro Derivatives
NHCOCH,
4a, X = 4421 b, X = 5-C1 C , X = 6-C1 d,X=H
Carlos Corral,* Jaime Lissavetzky, and Gloria Quintanilla
Znstituto de Quimica Mgdica, Madrid-6, Spain Received November 25, 1981
The parent compound (1, X = H)of the 5,6-dihydrodibenzo[b,fl[1,4,5]thiadiazepinesystem has been of interest due to its potential aromatic character' and its acid-catalyzed reactions (benzidine rearrangement).2 It has also been used as a key intermediate in the synthesis of the sulfur-bridged analogue of the antiinflamatory compound phenylb~tazone.~
1
The first attempted ~ynthesesl*~ of this compound, based on the reductive cyclization of bis(o-nitrophenyl) sulfide, afforded it in very poor yield, and it was not until 1971that S ~ m a n tachieved ~.~ this synthesis in an acceptable yield, following a four-step procedure. In this paper, we report a new and apparently useful method for the preparation of substituted compounds 1 (X= electronegative group) and the corresponding dehydro compounds 7. The method is based on the previously reported synthesis' of 10-(acy1amino)phenothiazine derivatives 3 b y cyclization of compounds 2 via base-catalyzed Smiles rearrangement (Scheme I). It was considered that this cyclization procedure could be applied to compounds 4, which apparently meet the (1) N. L. Allinger and G . A. Youngdale, J. Am. Chem. Soc., 84,1020 (1962). (2)L. D. Hartung and H. J. Shine, J. Org. Chem., 34, 1013 (1969). (3) H.S. Lowrie, J. Med. Pharm. Chem., 5, 1362 (1962). (4)M.F. Grundon and B. T. Johnson, J. Chem. SOC.B , 253 (1966). (5)H.Harry Szmant and Y. L. Chow, J.Org. Chem., 36,2887(1971). (6)K. Michel and M. Matter, Helu. Chim. Acta, 44, 2204 (1961). (7)C.Corral, J. Lissavetzky,and G. Quintanilla,J.Heterocycl. Chem. 15,1137 (1978).
0022-3263/82/1947-2214$01.25/0
5a, X = 2-C1 b, X = 3 4 1 C . X = 4-C1 Table I. Properties and Yields of 2-Nitrophenyl 2-(a,P-Diacety1hydrazino)phenylSulfidesa compd X % yield mp,b "C ~
4a 4b 4c 4d
4-a 56-C1
a
H
91 89 85 78
204- 2 06 150-152 181-183 110-112
Satisfactory analyses (k0.3 for C, H, and N) were reported for all compounds in this table. Recrystallized from benzene. All these compounds showed the following common IR and NMR spectroscopic data: IR (Nujol): 3270-3260 (NH), 1720-1715, 1660-1655 (CsO), 1520-1510; 1345-1340 cm-' (NO,), NMR (Me,SO-d,)6 1.9-2.0(s, 3 H, CH,), 2.1 (s, 3 H, CH,), 6.8-7.9 (m, 6 or 7 H, aromatic protons), 8.2-8.4 (m, 1 H, H-3, aromatic proton), 8.5-8.9 (s, 1 H, NH). a
required conditions for the Smiles rearrangement and further cyclization to produce compounds 5 (Scheme 11). For reasons of simplicity, only the cases in which X in compound 4 is 4-C1,5-C1,6-C1, and H (Table I) have been studied, i.e., substitution by a weak electronegative atom ortho, meta, and para to the sulfur atom and in the unsubstituted compound. The reaction did not take place for compound 4 4 although no starting material was recovered. However, compounds 4a-c did react to give compounds 5a in 81% 0 1982 American Chemical Society
J. Org. Chem., Vol. 47,No. 11, 1982
Notes Table 11. Properties and Yields of 5,6-Diacetyl-5,6-dihydrodibenzo[b,fl[ 1,4,5]thiadiazepinesa
2215
Table 111. Properties and Yields of 5,6.Dihydrodibenzo[ b,fl[1,4,5]thiadiazepines (1) and Dibenzo[ b,fl[l,4,5]thiadiazepines (7)a %
compd X yield mp,b "C compd X la 2 4 1 81 144-146 7a 241 l b 3-C1 76 105-107 7b 3 4 1 7~ 4-C1 IC 4-C1 79 151-152 5 compd 5a 5b
X 2-C1 3-C1
5c 5d
4-C1 H
% yield 81 62 (from 4b), 44 (from 6 ) 78 0
mp,b "C 150-151 200-202 151-152
See footnote a of Table I. Recrystallized from benzene. All these compounds showed the following IR and NMR spectroscopic data: IR (Nujol) 1710-1700, 1685-1680 cm - * (C=O); NMR (deuteriochloroform ) 6 2.15-2.20 (s, 6 H, 2 CH,), 7.3-7.7 (m, 7 H, aromatic protons). yield, 5b in 62% yield, and 5c in 78% yield, respectively (Table 11). These findings are consistent with the inductive as well as the mesomeric effects of the chloro substituents. The first should reinforce the action of the 2-N02 group in compounds 4, making the charge on C-1 more positive and facilitating attack of the -NCOCH3 anion. The second should stabilize the transition state of the reaction. It is thus concluded that X must be a n electronegative substituent for the reaction to take place. T h a t a Smiles rearrangement preceeds the above cyclization reactions is shown by compound 6, which when
-hCOCH,
I
HNCOCH,
6
subjected to the same reaction conditions as before gave a 44% yield of a compound which was identical with that obtained by cyclization of 4b. The fact that 6 does cyclize and compound 4d does not seems to point to a decisive charge-stabilizing effect of the 4'-chloro substituent on the rearranged intermediate anion. Compounds 5 were easily hydrolyzed to 1 by refluxing under nitrogen in aqueous alcoholic potassium hydroxide. The hydrazo compounds 1 in ethanolic solution were oxidized spontaneously a n d quantitatively to the corresponding 7.
7
This oxidation can be accelerated by bubbling air into the ethanolic solutions containing traces of potassium hydroxide.
Experimental Section Melting points were determined on a Gallenkamp capillary apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 257 spectrometer. Proton nuclear magnetic resonance were recorded on a Perkin-Elmer R-12 spectrometer
mp,C "C 92-94 127-128 84-85
a See footnote a of Table I. Recrystallized from ethanol. All these compounds showed similar IR and the following common IR and NMR spectroscopic data: IR (Nujol) 3260, 3160 cm-' (NHNH);NMR (deuteriochlo oform) 6 5.8-6.3 (m, 2 H, NHNH), 6.8-7.7 ( m , 7 H, aromatic protons). Recrystallized from ethanol. All these compounds showed similar IR and the following common NMR spectroscopic data: NMR (deuteriochloroform) 6 7.3-7.7 (aromatic protons).
(Me4Sias an internal standard). Hydrazinodiphenyl sulfides were obtained as previously rep~rted.~ 2-Nitro-6-chlorophenyl 2-hydrazinophenyl sulfide was obtained according to this procedure as a yellow solid 54% yield; mp 102-103 "C (benzene);IR (Nujol) 3330,3300 (NHNH,), 1520, 1340 cm-' (N0,2); NMR (MezSO-d6) 6 3.1-3.6 (br m, 2 H, NH,), 6.7-7.7 (m, 6 H, aromatic protons), 8.20-8.35 (m, 1H, H-3, aromatic proton). Anal. Calcd for C12H10ClN302S: C, 48.74; H, 3.38; N, 14.21. Found: C, 48.81; H, 3.46; N, 14.39. 2-Nitrophenyl2-(a,@-Diacetyl) hydrazinophenyl Sulfides 4a-d a n d 6. General Procedure. To a suspension of 0.1 mol of the corresponding hydrazine in 120 mL of anhydrous benzene was added 0.2 mol (14.3 mL) of acetyl chloride dropwise. The reaction mixture was refluxed for 3 h and allowed to stand overnight at room temperature. The yellow solids so formed were filtered and recrystallized from benzene. Properties and yields of compounds 4a-d are shown in Table I. Compound 6 was also obtained as a yellow solid: mp 163-164 "C (benzene);82% yield; IR (Nujol) 3270 (NH), 1720,1670 cm-' (C=O), 1520, 1340 (NO,); NMR (Me2SO-d6)6 1.9 (s, 3 H, CH,), 2.1 (9, 3 H, CH3), 6.8-7.8 (m, 6 H, aromatic protons), 8.3 (m, 1 H, H-3, aromatic proton), 8.7 (s, 1 H, NH). 5,6-Diacetyl-5,6-dihydrodibenzo[ b ,fl[1,4,5]thiadiazepines (5). General Procedure. Anhydrous potassium carbonate (1.0 g, 0.01 mol) was added to a vigorously stirred solution of the corresponding 2-nitrophenyl 2-(a,fi-diacetylhydrazinophenyl sulfide (0.01 mol) in 20 mL of N,N-dimethylformamide. The reaction mixture was heated under reflux for 15 min, cooled to room temperature, and poured into water. The solid thus obtained was filtered, dried, and recrystallized from benzene. Properties and yields of compounds 5 are shown in Table 11. 5,6-Dihydrodibenzo[bfJ[ 1,4,5]thiadiazepines (1). General Procedure. The corresponding compound 5 (3.3g, 0.01 mol) was dissolved in 40 mL of ethanol containing 0.03 mol of potassium hydroxide. The reaction mixture was refluxed for 3 h under nitrogen. After the mixture cooled, a colorless solid crystallized which was washed with ethanol, dried, and recrystallized from ethanol. Properties and yields of compound 1 are shown in Table 111. Dibenzo[bfl[ 1,4,5]thiadiazepines (7). General Procedure. Air was bubbled into an ethanolic solution of the corresponding compound 1 containing traces of sodium hydroxide, and the crystallineyellow solid which formed was filtered and washed with ethanol. Properties of compounds 7 are shown in Table 111.
Acknowledgment. We are indebted to E. Alvarez Frejo for his aid in a part of this work a n d t o our Department of Analysis and Instrumental Techniques for all the analytical a n d spectroscopic data. Registry No. la, 71693-43-1;lb, 81246-22-2;IC,81246-23-3;48, 71693-41-9; 4b, 81246-24-4; 412, 81246-25-5; 4d, 81246-26-6; 5a, 71693-42-0;5b, 81246-27-7;5c, 81246-28-8;6,81246-29-9; 7a, 8124630-2; 7b, 81246-31-3; 7c, 81246-32-4; 2-nitro-6-chlorophenyl-2'hydrazine-phenyl sulfide, 81246-33-5.
